Most young diabetics and many older patients will have their quality of life degraded and their lives shortened by complications of diabetes affecting the retina, nerves and kidneys. One long-range objective of this research is to identify patients at high risk of developing these microvascular complications, and to seek methods to reduce that risk. There is a close association of increased levels of inactive renin in plasma and of albumin in urine with the prevalence of microvascular complications in diabetes mellitus. Our first objective in a prospective study of 100 patients with uncomplicated diabetes is to determine whether an increased level of plasma inactive renin can predict the appearance of microvascular complications. Measurement of urine albumin by radioimmunoassay will also be made and the types of complications which appear in patients with abnormalities in plasma and/or urine will be compared. Treatments which lower plasma inactive renin or urine albumin have been identified, but there is a need to test them in larger numbers of patients before the appearance of complications, in order to establish that the incidence of complications can be modified. The cause of increased plasma inactive renin in diabetes is still uncertain. Additional observations will be made on the inactivation of cathepsin B by non-enzymatic glycosylation, and its possible role in the processing of prorenin to active renin will be explored. As the remarkable increase of plasma inactive renin, which occurs in the early weeks of pregnancy, remains to be explained, its connection with the secretory products of the chorion will be investigated. The inactive renin of early pregnancy plasma will be tested for the presence of the non-glycoprotein inactive renin secreted by the chorion into amniotic fluid. Plasma inactive renin will be measured in non-pregnant patients receiving exogenous human chorionic gonadotropin as therapy, as well as in patients with high endogenous levels arising from tumors. Pregnant diabetic women have extremely high levels of plasma inactive renin, whose significance is not understood: basic information, such as the effect of improved regulation of plasma glucose, will be sought and correlated with the clinical course and success of pregnancy.